Background

Because of the wide variability of pulmonary blood supply, diagnosis and surgical management of tetralogy of Fallot (TOF) with pulmonary atresia (PA) is more difficult than that of classic tetralogy of Fallot,
[1] and therefore, it is worthy of separate consideration.

Tetralogy of Fallot is composed of a malaligned ventricular septal defect (VSD), anterior shift of the aorta over the VSD (overriding aorta), obstruction of the right ventricular outflow tract, and right ventricular hypertrophy (see the following video). Pulmonary atresia with VSD is considered the extreme end of the anatomic spectrum of tetralogy of Fallot.

Parasternal long axis two-dimensional echocardiographic image demonstrating a large malalignment ventricular septal defect with overriding of the aorta over the ventricular septum.

Epidemiology

Tetralogy of Fallot with pulmonary atresia accounts for about 2% of congenital heart disease. The Baltimore Washington Infant study reported an incidence of tetralogy of Fallot with pulmonary atresia of 0.07 case per 1000 live births. Tetralogy of Fallot with pulmonary atresia accounted for 20.3% of all forms of tetralogy of Fallot.
[2]

There is no known race or sex predilection for tetralogy of Fallot with pulmonary atresia. This condition may become symptomatic at birth in most cases as the ductus arteriosus closes, although a delayed diagnosis may occur when additional sources of pulmonary blood flow besides the ductus arteriosus are present.

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Anatomy

The lungs develop from the foregut and carry their nutrient supply from the paired dorsal aortae. The paired sixth aortic arches also give rise to branches that form an anastomosis with the pulmonary vascular tree at 27 days' gestation. Over time, the branches from the descending thoracic arch become smaller, and the sixth aortic arch becomes larger.

The aorta and pulmonary arteries form from the distal bulbus cordis and the truncus arteriosus, which are positioned above the right ventricle. The bulbotruncal ridges separate the great arteries, and the aortic component posteriorly rotates. However, faulty rotation of the bulbus-truncus in tetralogy of Fallot (TOF) results in incomplete transfer of the aorta above the left ventricle. Malalignment of the infundibular septum to the trabecular septum is present, resulting in a malalignment ventricular septal defect (VSD).

Anterior displacement of the bulbotruncal region has been postulated to cause the infundibular stenosis. Another theory that has been suggested to cause tetralogy of Fallot is underdevelopment of the subpulmonic infundibulum that results in maldevelopment of the conal septum. Little or no evidence supports this hypothesis.

The anatomy of the pulmonary arteries and the source of pulmonary artery blood supply may widely vary in tetralogy of Fallot with pulmonary atresia (TOF-PA).
[3] Persistence of descending thoracic branches accounts for the abnormal pulmonary arterial supply in this condition. Major aortopulmonary collateral arteries (MAPCAs) may anastomose at any site in the pulmonary vascular tree. Most frequently, the right and left pulmonary arteries are patent and maintain free communication with each other and are therefore termed confluent pulmonary arteries. The pulmonary arteries may also be hypoplastic and nonconfluent with no antegrade pulmonary blood flow present from the right ventricle to the pulmonary arteries. The ductus arteriosus is an important source of blood supply to the central branch pulmonary arteries—and when absent indicates the present of MAPCAs.
[4]

Classification of pulmonary atresia with VSD depends on the predominant source of blood supply to the bronchopulmonary segments. These range from the native confluent, and possibly absent, central pulmonary arteries supplied solely by the ductus arteriosus to nonconfluent pulmonary arteries, with multiple major aortopulmonary collateral vessels supplying pulmonary blood flow.

Rare sources of pulmonary blood flow include an aortopulmonary window, a persistent fifth aortic arch, and coronary–to–pulmonary artery fistulae. Identification of the pulmonary arterial supply is essential in planning the type of surgical repair.

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Etiology

Many patients with tetralogy of Fallot with pulmonary atresia (TOF-PA) have associated syndromes and extracardiac malformations.

CATCH22 syndrome

Conotruncal cardiac malformations associated with a chromosome arm 22q11 deletion have been incorporated under an acronym of CATCH22 (cardiac defect, abnormal face, thymic hypoplasia, cleft palate, hypocalcemia, microdeletion of band 22q11). Patients with tetralogy of Fallot with pulmonary atresia have a higher incidence of this syndrome than patients with classic tetralogy of Fallot. The prevalence of deletion 22q11 is 16% in tetralogy of Fallot with pulmonary atresia with confluent pulmonary arteries and 41% in patients with tetralogy of Fallot with pulmonary atresia and multiple aortopulmonary collateral arteries.
[5] Surgical mortality has been reported to be greater among patients with tetralogy of Fallot with pulmonary atresia with a 22q11 deletion compared with patients with normal chromosomes, perhaps due to depressed immunologic status or other factors.
[6]

Maternal diabetes mellitus; maternal phenylketonuria; and maternal ingestion of retinoic acid, trimethadione, serotonin reuptake inhibitors, or sex hormones increase the risk of conotruncal abnormalities. Infants of mothers with diabetes mellitus have a 20-fold higher risk of these anomalies than infants of mothers without diabetes mellitus.

The recurrence risk of siblings with tetralogy of Fallot is 3-4%. The recurrence risk increases further if syndromic variants are present.

Variable patterns of inheritance may be observed.

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Prognosis

The prognosis of tetralogy of Fallot with pulmonary atresia (TOF-PA) depends on the specific anatomy and type of intervention. Survival before the advent of modern surgical techniques rarely occurred, with less than 5% of patients reaching age 25 years.
[8, 9] Survival into late adulthood without surgical intervention has been reported.
[10] Surgical morbidity and mortality and long-term survival have steadily improved into the current era, with most of these patients now surviving into adulthood.
[11] In patients with operable pulmonary arteries, survival rates with satisfactory quality of life reach 90%.

Long-term follow up data are not widely available; however, recent outcome does seem to be more favorable. Most patients who undergo placement of a right ventricle-to-pulmonary conduit require numerous conduit replacements throughout their lifetime, owing to progressive stenosis or insufficiency of the bioprosthetic valve.
[12, 13]

In patients with large aortopulmonary collaterals and excessive pulmonary blood flow, congestive heart failure (CHF) may result in failure to thrive (FTT) within the first few months of life.
[14]

Patients with tetralogy of Fallot and nonconfluent pulmonary arteries are subject to increased morbidity and mortality related to the frequent need for multiple cardiac surgeries. The risks of cardiopulmonary bypass and anesthesia are also present at each stage of the repair.

Surgical mortality has been reported to be greater among patients with tetralogy of Fallot with pulmonary atresia with a 22q11 deletion compared with patients with normal chromosomes.
[6]

In a retrospective observational study (1997-2014) of 48 adult patients with congenital heart disease who underwent heart transplantation, investigators reported that death was significantly associated with a minimum of 3 sternotomies and a MELD-XI (model of end-stage liver disease excluding international normalized ratio [INR]) score greater than 18.
[15] Both 1- and 5-year survival were 77%. The diagnoses included in the study included TOF-PA/double-outlet right ventricle (n=15), D-transposition of the great arteries (TGA) (n=10), tricuspid atresia/double-inlet left ventricle (n=9), ventricular or atrial septal defect (n=4), heterotaxy (n=3), congenitally corrected TGA (n=2), and other diagnoses (n=5).
[15]

Patient Education

Educate patients and/or their families about anatomic details and long-term prognosis, the potential need for multiple surgeries and catheterizations, and postoperative complications. Moreover, at all patient care visits, emphasize the need for bacterial endocarditis prophylaxis if clinically indicated.

Genetic counseling is strongly recommended in patients of childbearing age; the chance that patients with tetralogy of Fallot could have an offspring with congenital heart disease is as high as 15%. Patients with signficant residual hemodynamic abnormalities are advised to avoid pregnancy, because it carries significant mortality risk to both the mother and fetus.

Exercise tolerance and need for restrictions on physical activity depend on the type of repair and hemodynamic state of the patient. Exercise recommendations must be tailored to individual patients by considering the presence of cyanosis, right ventricular hypertension, right ventricular dysfunction, or dysrhythmias. Patients with cyanosis have significantly limited exercise capacity.

Children and adults who have had complete repair of tetralogy of Fallot with pulmonary atresia may have limited exercise tolerance due to ventricular dysfunction, chronotropic impairment, right ventricular outflow tract obstruction/valve insufficiency, or distal pulmonary artery stenoses.